Comparison of the Effect of High and Low Doses of Adrenocorticotropic Hormone (ACTH) in the Management of Infantile Spasms.

Objectives Infantile spasms can have irrecoverable adverse effects on a child’s brain. Adrenocorticotropic hormone (ACTH) is the most common first-line medication for the treatment of infantile spasms. However, the suitable dose and duration of treatment continue to be debated among specialists. Since high doses of ACTH, which are commonly used, can produce more side effects, lower doses are preferred. The aim of this study was to determine the effect and extent of complications caused by high and low doses of ACTH in children with infantile spasms. Materials & Methods This clinical trial was performed on 32 infants with infantile spasms, aged 1.5-18 months. The subjects were divided into high- and low-dose ACTH groups. Treatment continued for two months. The therapeutic effects and complications were then compared over 18 months. Results The results indicated no significant difference between the groups in terms of the short-term prognosis of convulsions, final prognosis of patients with spasm relapse, EEG changes after treatment, and post-treatment development of hypertension. On the other hand, there was a significant difference in the frequency distribution of restlessness intensity and becoming Cushingoid, which were more frequent in the high-dose group. Conclusion: The results indicated that high- and low-dose ACTH are equally effective in controlling spasms, yet the low dose causes fewer side effects.


Introduction
Infantile spasms are one of the most common convulsive syndromes in childhood (1)(2)(3). Children who are diagnosed with these spasms are within the age range of two months to less than one year (4,5). The peak incidence of these spasms occurs between three and seven months (50-77%), and occurrence is rare after 18 months of age (6). In half of patients, cognitive development is normal until the onset of convulsions, while cognitive delay has been observed in others (7,8). The approximate incidence of this condition is 2-5 infants out of every 10,000 successful births (9). Infantile spasms at older age evolve into Lennox-Gastaut syndrome; therefore, this epileptic pattern is not observed at older age (10). Etiologically, these convulsions are categorized into symptomatic, crypto-genetic, and idiopathic (11,12).
In terms of diagnostic measures, a complete awake and asleep electroencephalography (EEG) can detect the presence of hypsarrhythmia in 50-75% of cases as very high and low voltage waves across all cortical regions (13)(14)(15). Magnetic resonance imaging (MRI) is also helpful in diagnosing intracerebral lesions, which can predispose an infant to infantile spasms (16). Mental retardation occurs in 75% of afflicted infants and cerebral palsy in 50% (17). Statistically, five out of every 100 children with infantile spasms do not survive for more than five years (18). Less than half of patients with infantile spasms do not experience any attacks using medications (12). Diagnosis of infantile spasms, especially the cryptogenetic and idiopathic types, is a medical emergency, as delay in diagnosis for three weeks or longer affects the long-term prognosis (19). Therapeutically, various agents are used, but no medication has proven to be 100% effective so far.
Corticosteroids are the most common form of treatment for infantile spasm, with adrenocorticotropic hormone (ACTH) being the first-line medication (20,21). Vigabatrin is the first-line medication for children with tuberous sclerosis and infantile spasms (22). There are controversies regarding the suitable dose and duration of treatment using ACTH among specialists. Since high doses of this drug, which are commonly used, cause more side effects, lower doses are preferred (23,24). The aim of this study was to determine the effects and side effects of high-and low-dose ACTH treatments in children with infantile spasms.

Materials & Methods
The subjects were selected among 1.5-to 18-month-old infants with infantile spasms, who were referred to the pediatric neurological clinic

Results
In this study, 32 patients were investigated during 18 months. No patient was excluded during the study.
Both groups included the same number of patients.
In terms of gender, it was found that infantile spasms were slightly more frequent in boys (56%).
The mean and standard deviation of infants' age in the high-dose and low-dose groups were 8.2±2.6 and 5.2±6.6 months, respectively. The results of t-test indicated a significant difference in the mean age of the groups, but no significant difference was found in the onset of infantile spasms or onset of treatment between the two groups. The results of t-test indicated no significant difference regarding the type of infantile spasm (cryptogenic or symptomatic) between the groups.
The results of this study showed that patients with infantile spasms had a mean age of four months. On average, they were diagnosed and treated after about two months of delay from the onset of symptoms.
In terms of clinical type, 59% of the patients were categorized as flexor, 28% as extensor-flexor, and 13% as extensor. Etiologically, 25 (78%) patients had the symptomatic disease, and its prevalence was not significantly different between the groups.  Table 1). There was no significant difference in EEG changes after treatment between the groups. There was also no significant difference in the incidence of hypertension throughout the treatment (P=0.5). On the other hand, there was a significant difference in the incidence of restlessness and the associated sleep disorders (P=0.002). There was also a significant difference in terms of the incidence of becoming Cushingoid (P=0.04).

Discussion
Previous studies have shown that use of high-dose ACTH is associated with more side effects and less desirable therapeutic outcomes, compared to its lower doses (25)(26)(27)

In conclusion
the results indicated that high-and low-dose ACTH are equally effective in controlling spasms. Lower doses of ACTH did not result in the further relapse of convulsions, but it was found that use of higher doses increased the incidence of side effects. Lack of difference in the therapeutic outcomes between the groups, along with the reduction of side effects in the low-dose group, justifies the use of low-dose ACTH for controlling infantile spasms.